61- Localisation des lésionsSuperposition des lésions cérébralesqui entraînent une hémiplégiePatients were referred to our clinic because of their first completed ischemic stroke. Inclusion criteria for this study were acute hemiplegia or severe hemiparesis with complete loss of fractionated movements of the affected hand and presence of only 1 brain lesion, as evident from magnetic resonance (MR) images.Additionally, the lesions of each patient were evaluated morphometrically to determine the lesion size and were superimposed on each other to create a mean lesion mapFigure 1. Location of spatially standardized brain lesions in the stereotactic atlas.19 Shading intensity signifies the degree of overlap. Arrowheads localize the central sulcus. The z values indicate the level dorsal to the intercommissural plane.Seitz et al.Arch Neurol. 1998;55:

7localisation de la lésion et pronosticCrafton et al. Brain : ;En haut corrélation chez 21 patients, en bas exemple chez le sujet indiqué.Fonction plus altérée si la lésion intéresse la région de la main.Fig. 2 (A) Infarct volume (top left) and fraction of hand motor map injured by stroke (top right) each show a significant inverse relationship with pegboard performance by the affected hand (normalized to pegboard results for the unaffected hand). However, correlation is stronger and more significant in the latter case. Note that injury to >37% of the hand motor map was associated with total loss of hand motor function. The arrow indicates the patient whose images are displayed below. (B) Images from a patient whose stroke was mild–moderate in size (33 cm3), but injured 35% of the hand motor area and was associated with total loss of hand motor function.Volume of injury is often used to describe a brain insult. However, this approach assumes cortical equivalency and ignores the special importance that certain cortical regions have in the generation of behaviour. We hypothesized that incorporating knowledge of normal brain functional anatomy into the description of a motor cortex injury would provide an improved framework for understanding consequent behavioural effects. Anatomical scanning was performed in 21 patients with a chronic cortical stroke that involved the sensorimotor cortex. Functional MRI (fMRI) was used to generate separate average activation maps for four tasks including hand, shoulder and face motor tasks in 14 controls. For each task, group average maps for contralateral sensorimotor cortex activation were generated. Injury to these maps was measured by superimposing each patient’s infarct. These measurements were then correlated with behavioural assessments. In bivariate analyses, injury to fMRI maps correlated with behavioural assessments more strongly than total infarct volume. For example, performance on the Purdue pegboard test by the stroke-affected hand correlated with the fraction of hand motor map injured (r = –0.79) more strongly than with infarct volume (r = –0.60). In multiple linear regression analyses, measures of functional map injury, but not infarct volume, remained as significant explanatory variables for behavioural assessments. Injury to >37% of the hand motor map was associated with total loss of hand motor function. Hand and shoulder motor maps showed considerable spatial overlap (63%) and similar behavioural consequences of injury to each map, while hand and face motor maps showed limited overlap (10.4%) and disparate behavioural consequences of injury to each map. Lesion effects support current models of broad, rather than focal, sensorimotor cortex somatotopic representation. In the current cross-sectional study, incorporating an understanding of normal tissue function into lesion measurement provided improved insights into the behavioural consequences of focal brain injury.

11Allongement de la durée de la période de silence2 patients avec des MEP subnormaux et une SP prolongée.Evolution parallèle de la SP et du niveau fonctionnel.La déficience pourrait être en partie due à une hyperactivité de phénomènes inhibiteurs intracorticaux.Classen et al.Brain. 1997, 120 :Following transcranial magnetic stimulation (TMS) at stimulation strength of 1.5 times the resting motor threshold, a silent period (SP) of approximately 180 ms duration can be observed in surface EMG-registrations of tonically activated small hand muscles. This SP is believed to be generated cortically and can be prolonged in stroke patients, but it is not known whether a prolongation of the SP has any functional significance. In order to answer the question of whether enhanced cortical inhibition can contribute to pathophysiology of motor dysfunction we studied stroke patients with clearly prolonged SP durations in the first dorsal interosseus muscle (> 2 times that of the intact side), but with normal magnetically evoked motor potentials. Sixteen patients out of a cohort of 174 consecutive patients presenting with acute hemiparetic stroke fulfilled the inclusion criteria. Serial TMS investigations were performed for up to 2 years post-stroke. In all patients, the SP duration decreased in parallel with clinical improvement. In two patients, intermittent clinical deterioration was accompanied by an increase in the SP duration. In four patients, in addition to a markedly prolonged SP duration, the phenomenon of a complete inability to initiate voluntary muscle activity for several seconds, following TMS, could be observed in a number of trials ('motor arrest'). Detailed clinical analysis revealed that, in addition to hemiparesis, distinct motor disturbances in patients with SP prolongation could be observed. These motor disturbances resembled those of motor neglect and were characterized by motivationally dependent under-utilization of the affected arm, impairment of movement initiation, inability to maintain a constant force level and to scale forces, and impairment of individual finger movements. In 12 of the 16 patients at least one additional behavioural manifestation of neglect was present. We suggest that in stroke patients severe motor dysfunction may be caused by hyperactivity of cortical inhibitory interneurons rather than by direct lesions of descending motor tracts. Cortical hyperinhibition may, in turn, result from damage to any of a number of afferent pathways to the motor cortex which modulate local interneuronal activity.

15Plasticité corticale due à l'entraînementFigure 3. A representative SI hand zone map, here shown for an owl monkey case (OM2258). (A) Sampling microelectrode penetration sites are represented by black dots, drawn over the outline of a cartoon map summarizing the representation of different skin surfaces on the hand. Cutaneous receptive fields were defined for deep layer 3–4 neurons by careful hand exploration at each of these sites. Receptive fields were drawn on computer images of the glabrous and dorsal surfaces of the hand. (B) Map boundaries were drawn between sampling grid points for which receptive fields were centered on different skin surfaces. When receptive fields overlapped between different designated skin surfaces, e.g. between the distal (d) and middle (m) segment of the five fingers (1–5), the boundary reflected the extent of receptive field overlap onto those different skin surfaces. Note that this map also included a complete reconstruction of the representation of the hand in cortical area 1 (toward the left in these cartoons). Other abbreviations: p, proximal digit segment; P1–P4, palmar pads at the bases of the digits; H, hypothenar eminence; Pi, insular pads in the center of the palm; W, wrist; NCR, sites at which no cutaneous response could be evoked. Dorsal skin representational zones are shaded. The arrows mark the approximate line of reversal in receptive field sequences that functionally distinguish the area 3b/area 1 border (Merzenich et al., 1978).Singe entraîné dans une tâche comportementale significative :- élargissement de la carte du doigt stimulé- rétrécissement des champs récepteurs.Jenkins et al. J. Neurophysiol : Functional reorganization of primary somatosensory cortex in adult owl monkeys after behaviorally controlled tactile stimulation.

17Plasticité de la carte motrice de la main après lésion corticaleFigure 5. Summary of functional remodeling of the hand representation in primary motor cortex after a stroke-like injury. Data were derived from hundreds of microelectrode penetrations using microstimulation techniques to determine evoked movements in anesthetized monkeys. These studies, and others like them, demonstrate that the uninjured tissue adjacent to a cortical injury undergoes functional reorganization that can be modulated by postinjury behavioral training. (Reprinted by permission from Stockton Press.[153])Nudo RJ, Wise BM, SiFuentes F, Milliken GW. Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 1996;272:Adapté: Nudo et al. Role of adaptive plasticity in recovery of function after damage to motor cortex. Muscle Nerve Aug;24(8):

18Rôle des stratégies motricesLes singes peuvent utiliser des stratégies motrices différentes.Friel KM, Nudo RJ. Recovery of motor function after focal cortical injury in primates: compensatory movement patterns used during rehabilitative training. Somatosens Mot Res. 1998;The recovery of skilled hand use after cortical injury was assessed in adult squirrel monkeys. Specific movement patterns used to perform a motor task requiring fine manual skill were analyzed before and after a small ischemic infarct ( mm2) to the electrophysiologically identified hand area of the primary motor cortex (M1). After 1-3 weeks of pre-infarct training, each monkey stereotypically used one specific movement pattern to retrieve food pellets. After injury to the hand area of M1, the monkeys were required to retrieve the pellets using their impaired forelimb. Immediately after the injury, the number of finger flexions used by the monkeys to retrieve the pellets increased, indicating a deficit in skilled finger use. After approximately 1 month of rehabilitative training, skilled use of the fingers appeared to recover, indicated by a reduction in the number of finger flexions per retrieval. The monkeys again retrieved the pellets using one specific movement pattern in most trials. Despite the apparent recovery of skilled finger use after rehabilitative training, three of five monkeys retrieved the pellets using stereotypic movement patterns different from those used before the injury. Thus, this study provides evidence that compensatory movement patterns are used in the recovery of motor function following cortical injury, even after relatively small lesions that produce mild, transient deficits in motor performance. Examination of electrophysiological maps of evoked movements suggests that the mode of recovery (re-acquisition of pre-infarct movement strategies vs development of compensatory movement strategies) may be related to the relative size of the lesion and its specific location within the M1 hand representation.

22Suivi longitudinal: schémas évolutifsFeydy et al. 2002Différents schémas d’évolution vers la récupérationA: Initial focusing (M1 normal, PAQ.)B: Progressive focusing (M1 normal, POI)C: Persistent recruitment (M1 lesioned HEM)Figure 3. Three patterns of evolution of fMRI activation after MCA stroke and use of the affected hand for 3 different patients (all Rgood). A, Initial focusing in patient 3-PAQ with a lesion in the left frontal region not affecting the motor cortex (M1normal). Images (during 3 different sessions: 1/2/3 using the right hand) show an activation focused on SMC during the 3 fMRI sessions. Based on the averaged indexes, evolution was classified as initial focusing (IndexSMC 1/2/3=0.62/0.81/0.85; IndexHEM 1/2/3=0.93/1/1; threshold, P<0.001). B, Progressive focusing for patient 1-POI without lesion of the motor cortex (M1normal; lesion shown in Figure 1). In the first session (using the right hand), the activation involves SMC on both sides (with a predominance of ipsilateral SMC) and other ipsilateral regions (SMA, and premotor areas). In the second session, the SMC is active only on the contralateral side (associated with SMA). In the final session, only contralateral SMC activation is present. Classification was progressive focusing (IndexSMC 1/2/3=0.34/0.75/0.70; IndexHEM 1/2/3=-0.04/0.70/0.53; threshold, P<0.001). C, Persistent recruitment in patient 11-HEM with a small limited lesion of the motor cortex (M1lesioned). In the first session (using the left hand), the activation involved the SMC on both sides (with a predominance of the ipsilateral SMC) and other ipsilateral regions (SMA and premotor areas). In the second and third sessions, both contralateral and ipsilateral SMCs are activated. Classification was persistent recruitment (IndexSMC 1/2/3=0.23/0.29/0.34; IndexHEM 1/2/3=0.22/0.28/0.17; threshold, P<0.0001).

24Plasticité inter-cartes : role de l’aire prémotrice.2 singesM1 main coté lésé (C)M1 proximal coté lésé (D)M1 main coté intact (E)M1 proximal coté intact (F)PM (d et v) coté lésé (G)PMd coté lésé (H)PMv coté lésé (I)PM (d et v) coté intact (J)M1 main coté lésé (K)PM (d et v) coté lésé (L)M1 main coté intact (M): Exp Brain Res Sep; 128(1-2): Mechanisms of recovery of dexterity following unilateral lesion of the sensorimotor cortex in adult monkeys. Liu Y, Rouiller EM.The mechanisms of recovery of manual dexterity after unilateral lesion of the sensorimotor cortex in adult primates remain a matter of debate. It has been proposed that the cortical zone adjacent to the lesion may take over part of the function of the damaged cortex. To investigate further this possibility, two adult (4-5 years old) macaque monkeys were trained to perform a natural precision-grip task to assess hand dexterity. Intracortical microstimulations (ICMS) were used to map the hand area in M1 on both hemispheres. Ibotenic acid was then injected intracortically to damage the representation in M1 of the preferred hand. Subsequent histological analysis indicated that the hand representation in M1 was indeed lesioned, but, due to a spread of ibotenic acid, the lesion encroached a significant extent of the hand representation in the primary somatosensory cortex. A few minutes after infusion of ibotenic acid, there was a complete loss of dexterity of the preferred hand, which lasted for 1-2 months. Later, a progressive functional recovery of the affected hand took place over a 3- to 4-month period, reaching a stable level corresponding to 30% of the pre-lesion behavioral score. ICMS remapping, conducted nine months after the lesion, revealed that stimulation of the intact or lesioned M1 did not induce any visible movement of the recovered hand. The M1 hand representation on the intact hemisphere was similar to that observed before the lesion. Transient inactivation of the M1 hand/arm areas or of the dorsal and ventral premotor cortical areas (PM) on both hemispheres was undertaken by using microinjections of the GABA-agonist muscimol. Inactivations of M1 had no effect. Inhibition of PM in the damaged hemisphere suppressed the recovered manual dexterity of the affected hand. These results suggest that PM plays a significant role in the incomplete functional recovery of hand dexterity following unilateral damage of the sensorimotor cortex in adult monkeys.learning, is a prerequisite factor in driving representational plasticity in M1.Liu Y, Rouiller EM, Exp Brain Res :"Our results are consistent with the hypothesis that the dorsal premotor cortex of the affected hemisphere can reorganize to control basic parameters of movement usually assigned to M1 function. "

25Plasticité inter-cartes après lésion corticaleCarte de l’aire prémotriceavant et 1 semaine aprèsune lésion de l’aire motrice.Augmentation de l’aire de la main.FIG. 4. Reorganization of hand representations in the ventral premotor cortex before and after a focal ischemic infarct in the hand representation of primary motor cortex. Left: schematic representation of the forebrain of the squirrel monkey from a lateral view showing the location of the M1 distal forelimb area (dfl) and the location of ventral premotor cortex (PMV). Right: results of ICMS mapping of the PMV hand area in 1 monkey (9406) before (top) and 12 wk after ischemic infarct in the M1 hand area (bottom). Circles represent the location of microelectrode penetrations and colors represent the movement(s) evoked by near-threshold electrical stimulation (<30 µA) at that site. In this animal (9406), the infarct damaged 79% of the preinfarct M1 hand representation area and postinfarct PMV mapping revealed a 45% increase in the PMV hand representation. In each animal, an increase in the area of distal forelimb movement representation occurred 12 wk after infarct in M1. Scale bar = 1 mm.FIG. 5. The results of ICMS mapping of the PMV hand area before and 3 mo after the ischemic infarct in 4 monkeys. ICMS mapping revealed a net expansion in the PMV hand representation in each monkey. Different colors represent the evoked movement(s) of particular body parts at near threshold levels at each penetration site. Scale bars = 1 mm.FIG. 6. The results of ICMS mapping of the M1 and PMV hand areas before and 3 mo after the ischemic infarct. Left:M1 hand area. The results revealed decreases in the M1 hand area in all 5 animals. Although the entire hand area was targeted for infarct, partial retention of spared hand area was seen in all 5. The decrease in absolute M1 hand area ranged from 6.0 mm2 in 1 animal (9406), to 16.6 mm2 in another (0004). Right: PMV hand area. There was an increase in the total area of the hand representation in PMV at 3 mo postinfarct in all 5 animals. This increase ranged from 0.3 (9902) to 1.9 mm2 (0003).Augmentation de l’aire PMv en rapport avec l’extension de la lésion de M1 (chez 5 singes)Frost et al. J Neurophysiol 89: , 2003Reorganization of Remote Cortical Regions After Ischemic Brain Injury: A Potential Substrate for Stroke Recovery

29Discuté chez l'adulteLa présence de MEP ipsi-latéraux est observée au début puis décroît avec la récupération.Une activation bilatérale est plutôt signe de forte déficience.Mais effet perturbant de la TMS sur PMD ipsi sur le temps de réaction.D'autant plus sensible que l'activation fMRI est bilatéraleJohansen-Berget al. The role of ipsilateral premotor cortex in hand movement after stroke. Proc Natl Acad Sci U S A Oct 29;99(22):(A: TMS sur PMd, B: TMS sur M1)Trait fin : patients, épais : validesMovement of an affected hand after stroke is associated with increased activation of ipsilateral motor cortical areas, suggesting that these motor areas in the undamaged hemisphere may adaptively compensate for damaged or disconnected regions. However, this adaptive compensation has not yet been demonstrated directly. Here we used transcranial magnetic stimulation (TMS) to interfere transiently with processing in the ipsilateral primary motor or dorsal premotor cortex (PMd) during finger movements. TMS had a greater effect on patients than controls in a manner that depended on the site, hemisphere, and time of stimulation. In patients with right hemiparesis (but not in healthy controls), TMS applied to PMd early (100 ms) after the cue to move slowed simple reaction-time finger movements by 12% compared with controls. The relative slowing of movements with ipsilateral PMd stimulation in patients correlated with the degree of motor impairment, suggesting that functional recruitment of ipsilateral motor areas was greatest in the more impaired patients. We also used functional magnetic resonance imaging to monitor brain activity in these subjects as they performed the same movements. Slowing of reaction time after premotor cortex TMS in the patients correlated inversely with the relative hemispheric lateralization of functional magnetic resonance imaging activation in PMd. This inverse correlation suggests that the increased activation in ipsilateral cortical motor areas during movements of a paretic hand, shown in this and previous functional imaging studies, represents a functionally relevant, adaptive response to the associated brain injury.Variability occurred in the relative lateralization of fMRI activation in patients. (A and B) Representative activation maps for a simple RT task versus restfor two individual patients. Bilateral motor cortex activation was most common in more impaired patients (e.g., A, illustrating results from a patient withimpairment score of 17.9). Predominantly contralateral activation (i.e., similar to the control pattern) was most common in less impaired patients (e.g., B, froma patient with impairment score of 6.2). We found a correlation between impairment and lateralization of fMRI activity (C) fMRI data are thresholded atZ 3.1, and a cluster extent threshold of P

40Résultats de la "Constraint Therapy"- Amélioration fonctionnelle- Parallèle à une modification de l’excitabilité corticale.Background and Purpose—Injury-induced cortical reorganization is a widely recognized phenomenon. In contrast, there is almost no information on treatment-induced plastic changes in the human brain. The aim of the present study was to evaluate reorganization in the motor cortex of stroke patients that was induced with an efficacious rehabilitation treatment.Methods—We used focal transcranial magnetic stimulation to map the cortical motor output area of a hand muscle on both sides in 13 stroke patients in the chronic stage of their illness before and after a 12-day-period of constraint-induced movement therapy.Results—Before treatment, the cortical representation area of the affected hand muscle was significantly smaller than the contralateral side. After treatment, the muscle output area size in the affected hemisphere was significantly enlarged, corresponding to a greatly improved motor performance of the paretic limb. Shifts of the center of the output map in the affected hemisphere suggested the recruitment of adjacent brain areas. In follow-up examinations up to 6 months after treatment, motor performance remained at a high level, whereas the cortical area sizes in the 2 hemispheres became almost identical, representing a return of the balance of excitability between the 2 hemispheres toward a normal condition.Conclusions—This is the first demonstration in humans of a long-term alteration in brain function associated with a therapy-induced improvement in the rehabilitation of movement after neurological injury.Treatment-Induced Cortical Reorganization After Stroke in HumansLiepert, et al. Stroke. 2000;31:1210.

42Tentative de récapitulationChanges in bilateral brain areas after unilateral stroke have been grouped into 3 time periods. First, in the initial hours/days after a stroke, brain function and behavior can be globally deranged, and few restorative structural changes have started. Second, a period of growth then begins, lasting several weeks. Structural and functional changes in the contralesional hemisphere precede those of the ipsilesional hemisphere, and at such times activity in relevant contralesional areas can even exceed activity in the lesion hemisphere. This growth-related period may be a key target for certain restorative therapies. Third, subsequently, there is pruning, reduction in functional overactivation, and establishment of a static pattern of brain activity and behavior. The final pattern may nevertheless remain accessible to plasticity-inducing, clinically meaningful interventions. An excess of growth followed by pruning has precedence in human neurobiology, being a recapitulation of normal developmental events. Supranormal and subnormal activity levels in the ipsilesional and contralesional hemispheres correlate with features of behavioral outcome in specific patient populations, as described above. CBF indicates cerebral blood flow; CMRO2, cerebral metabolic rate of oxygen; and Rx, treatment.